Ondansetron is a pharmaceutically active agent commonly used for the treatment of nausea and vomiting, particularly associated with chemotherapy in cancer treatments. In currently marketed pharmaceutical compositions, ondansetron is used as free base in rapidly dissolvable tablets and as hydrochloride salt in injections, tablets and oral solutions. The chemical name of Ondansetron is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl)-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one and is represented by the structural formula given below:

Because Ondansetron molecule has a chiral carbon atom, it exists in two enantiomeric forms; however, racemic ondansetron is marketed so far. The molecule was first disclosed in the U.S. Pat. No. 4,695,578 in 1987. The '578 patent discloses many ways to prepare Ondansetron starting from a compound of general Formula II which in turn is prepared from 1,2,3,9-tetrahydro-9-methyl-4H-carbazole.
In another alternative, Ondansetron is prepared by N-methylation of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of Formula-VI with strong base like sodium hydride
and dimethylsulfate in solvents such as dimethyl formamide, THF or an aromatic hydrocarbon, toluene etc. The yield of this reaction is only about 21% since the activation of the ring nitrogen atom is difficult.
Yet another alternative preparation of Ondansetron is by Michael-type addition reaction of 2-methylimidazole to 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one of Formula-VIII which according to this patent is prepared from 3-[(trimethylamino)-methyl-1,2,3,9-tetrahydro-9-methyl]-4H-carbazol-4-one iodide (Formula VII) (Scheme II).

In one alternative, Ondansetron was prepared from hydrochloride salt of 3-[(dimethylamino)-methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of Formula-III by treating it with 2-methyl imidazole in a medium of solvent such as water or an alcohol or their mixture thereof at reflux temperatures for longer period of time like 20 to 47 hours. (Scheme 1)

The Starting compound of Formula-III was prepared by a Mannich reaction of 1,2,3,9-tetrahydro-9-methyl-4H-carbazole with N,N-dimethylamine hydrochloride and paraformaldehyde in a medium of glacial acetic acid at reflux temperature for long duration to give Formula III in very poor yields.

This particular reaction is carried out in solvent systems such as water, ethyl acetate, ketone e.g. acetone, MIBK and amides over a period of 20 hours resulting in 44% yield.
Yet another process disclosed in '578 is a substitution of chlorine in 3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of Formula IX using 2-methyl-imidazole in presence of strong bases. This reaction was carried out in solvents such as dimethyl formamide, alcohols etc. resulting in about 72% yield.

The '578 patent also talks about the oxidation of 2,3,4,9-tetrahydro-9-methyl-4-hydroxy-3-[(2-methyl-1H-imidazole-1-yl)methyl]-1H carbazol maleate of formula-XI using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dry THF for the preparation of Ondansetron which according to the patent resulted in about 55% yield.

U.S. Pat. No. 5,478,949 discloses a multi-step process for preparing Ondansetron by providing a novel intermediate compound of Formula XII which activates the methyl group which is alpha to the oxo group of the carbazolone to facilitate introduction of imidazole heterocyclic ring with 2-methylimidazole to give a compound of Formula XIII which is in-turn converted into ondansetron in 75 to 87.3% yields according to the patent. Although the reaction proceeds well according to the patent, the process suffers from increased number of stages and the overall yields were not significant in comparison with the product patent ('578 patent) process.

U.S. Pat. No. 6,388,091 discloses an improvement for preparing Ondansetron wherein a Silyl enol ether of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of Formula XIV is alkylated with 1-(N,N-dialkylaminomethyl)-2-methylimidazole of Formula-XV (Scheme III) in presence of an organic solvent such as MDC, chloroform, acetonitrile, THF, dioxane, toluene, DMF, ethanol or mixture thereof resulting in an yield range of 81 to 86%. The process improves the yield of ondansetron but it lacks industrial applicability. One of the reasons being Silyl reagents are costly. Apart from this; the 1-(N,N-dialkylaminomethyl)-2-methylimidazole reagent has to be prepared, since it is not a commercially available reagent and therefore increases the number of steps in the process.

In another prior art, U.S. Pat. No. 4,957,609, Ondansetron is prepared by a different route of synthesis wherein the last step is the closure of the central ring of 1,2,3,9-tetrahydrocarbazol-4-one ring system starting with a compound of Formula XVI where X is a hydrogen or a halogen atoms using copper or palladium catalyst. The solvent system used for the reaction includes DMF, N-methylpyrrolidone, HMPA, nitriles and alcohols. This process suffers from many disadvantages such as reaction specificity/regio-specificity in amino-methylation reaction and other side reactions and decomposition; accordingly the process is not suitable for industrial preparation of this pharmaceutical.

Yet another U.S. Pat. No. 4,739,072 describes another cyclization process for preparing Ondansetron wherein the catalyst is different than '609 patent. In this process, the cyclization of the starting material, a hydrazine of a Formula-XVII, is induced with a Lewis acid in an aqueous or an organic solvent medium. This process also has disadvantages from the point of view of industrial applicability similar to those discussed in the above prior art.

The alpha amino-methylation of 4-oxo group of 1,2,3,9-tetrahydrocarbazole-4-one still remains a major difficulty and Patent No. CN 1105364 addresses this problem and discloses a preparative method for Ondansetron by activation of alpha-position of 4-oxo positions by enamine formation (Formula-XIX) and subsequent reaction with 2-methylimidazole, again increasing the number of stages in the production of ondansetron.

Although various routes of synthesis available to a skilled synthetic chemist are disclosed in the product patent ('586 patent), several other prior arts (EP 59511, U.S. Pat. No. 4,983,621, EP191562, U.S. Pat. No. 4,822,881, KR923064, KR9832228, GB2152153821, ES2043535, RU2162695, RU2041876, CN1161966, CN1115760, CN1110970, CN1113239, CN1105364, CN1113913, CN1145902 etc.) are published and discuss improvements over the route disclosed in the said product patent and continued to work on to find improved process for Ondansetron of high purity in high yields.
WO 03093281 A1 discloses an improved process for preparation of Ondansetron over the processes disclosed in the '586 patent by introducing a solvent combination of water and dimethyl formamide instead of water alone in the trans-amination of compound of Formula-III with 2-methylimidazole and claimed to increase the yield from 80% to 96% but based on the penultimate intermediate 3-[(dimethylamine)methyl)]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one as starting material. Therefore the overall yield from the 1,2,3,9-tetrahydrocarbazole-4-one remains low.
It is apparent from the above discussion that considerable research is being carried out by synthetic chemists to develop a suitable industrial process for the preparation of Ondansetron to increase the yield and purity for which most of the synthetic routes were disclosed in the product patent itself. It can be understood that the major challenge in the preparative method is the introduction of side chain (methyl group) to the alpha position of the 4-oxo group of 1,2,3,9-tetrahydrocarbazole-4-one and the subsequent N-alkylation of 2-methylimidazole since most of the prior art patents concentrate their efforts on the final stage of the preparation of Ondansetron. The major drawback of most of the reported processes is that the Ondansetron prepared from the said intermediates of Formula-III, VIII and IX, results in lower yield having higher ratio of exo-methylene impurity apart from the difficulty in stirability of reaction mass due to tarry mass formation in amino-methylation reaction. Moreover the isolation of pure 3-[(dimethylamine)methyl)]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one is considerably difficult due to the complex nature of the reaction mass resulting from the reported prior art processes. This ultimately leads to very poor yield and quality of the intermediate resulting in lower overall yield/purity of the Ondansetron from the compound of Formula-IV. The maneuvering of the amino-methylation reaction on an industrial scale is also a major concern. The present inventors have invested considerable efforts to tackle the problems associated with preparative methods of Ondansetron and have come up with an improved process which is the subject of the present invention.